For those who are in the audience less familiar with the Dyne story, maybe talk about what you're trying to achieve, what you're working on, and the types of milestones we can expect over the next 12 to 24 months.
Yeah, happy to, Andrew. Thanks for having us, and we'll be making some forward-looking statements. Dyne was really built to deliver functional improvement for those suffering from neuromuscular diseases. It was all built and based on the notion that if we could target genetic medicines using the TFR1 receptor, using a Fab, a novel approach, that we could deliver enough genetic medicine to not only muscle, but to the CNS, and that you might actually get functional improvement in diseases like DM1 and DMD. Now, at this point, we're really a pure-play neuromuscular company focused on those diseases. When you talk about kind of milestones for 2026 and even through the rest of this year, the first major milestone will be DMD data readout, top-line registrational data for DMD in December. That takes us then into, and we're excited about that, by the way.
Hope we can talk some more about that. That takes us into 2026. In 2026, we have a BLA for DMD in Q2 of next year. We have two, I think, what will be field-defining phase three programs, one for DMD and another one for DM1. We will be, frankly, building out our organization to prepare for a launch. I will tell you, over the last year, Andrew, we've built out the management team to prepare for the launch, supply, commercial, et cetera, to launch our first product in early 2027, which will be our DMD product. I'll stop there.
Okay. I think the DMD readout is kind of sneaking up. Not many people are too well aware of that data set, but I think it'd be nice to talk a little bit about that. To begin, set us some context about this exon 51 market opportunity. How many patients are out there? We know Exondys 51, Sarepta's drug, is $500 million, doing $500 million right now. Talk about the market opportunity for your product, especially if it could prove ultimately superior to Exondys 51.
You know, it's an exciting time potentially for DMD. I know there's been really, over the last number of months, some disappointments. Gene therapy, there's been some setbacks there. And some of the latest data with naked PMOs has shown that functional kind of benefit has not been there. Our drug for DMD, exon 51, has been something that has been, as I described, targeting the muscles that matter for these patients. We have shown functional improvement through our multi-ascending dose cohort. If you look at that market for exon 51, that is the most prevalent of the genetic mutations within DMD. There are 1,500-1,600 patients. Four hundred or so, we think, are on Exondys 51. About 400.
We also think that there's probably 300 or 400 that had dropped off of Exondys 51 simply because kind of the functional benefit has been difficult to see, and it's also a weekly dose. We actually believe that clinicians and patients and patient advocates are waiting desperately for some medicine that has not only robust dystrophin, but shows functional improvement. Beyond the patients that we just talked about, there's probably another 700 or 800 patients that have done nothing except been able to take some steroids. They just haven't believed there's been a medicine for them. I think the market is ripe for conversion, particularly those that are on Exondys 51 now, but also to extend into those patients that have been looking for an alternative.
Makes sense. Especially if you do show superior dystrophin, ultimately functional benefits, what are you thinking about price? What are the bookends?
I think it's early for us to talk about price, but you know the baseline price that I think most would consider that we would consider is that Exondys 51 is roughly $1 million a patient. I mean, it's weight-based and $1 million a patient and very questionable efficacy. I would think of that as a base, but let's see our data and let's get a little closer to the market before we get to price.
Understood. The data's coming in Q4 any day now. I think maybe you've got it to December, if I'm not mistaken.
Yes, we have.
Okay. In December, how did you power the study on the primary endpoint of dystrophin? What did you power it to show? What do you think you need to fundamentally achieve for you to say, yeah, we have something just simply very different from Exondys 51, aside from the function side?
Yeah. So this study has been powered for dystrophin change from baseline. You know, I think if you talk about it from a regulatory accelerated approval standpoint, the historical standard has been Exondys 51, which I believe has shown roughly 0.3% improvement from baseline on dystrophin. You've seen our data, Andrew, up to 20 mg per kg, where we had seen about 3.7% mean change from baseline. So about 10x of what has ever been seen before with the PMO for exon 51. For accelerated approval, it is about change from baseline on dystrophin. We feel obviously very, very good about that based upon the data we've seen so far. In addition to that, what we'd love to see is the functional trends like we've shown and presented previously. That's everything from 10-meter walk run to time to rise, to NSAA, to stride velocity 95th centile.
Understood. Your mention of 3.7%, that's unadjusted dystrophin. Is the study powered to show unadjusted or adjusted or both?
Both. It can be either, but both. I'm glad you raised it. You know, we've used the unadjusted as a conservative measure. In that study, we were at 8.7% when you adjusted for muscle content. I don't think anybody's seen any numbers like that for exon 51. Keep in mind, that's at just six months. You take a biopsy at six months in these boys. If you do modeling, dystrophin has a half-life of roughly three to four months. You would expect significantly more dystrophin over time, but that's a great place to start even at six months.
In terms of the fundamental accelerated approval, will the FDA want simply dystrophin changes, or do they want you to show functional trends on top of that?
You know, the expectation is dystrophin change. That's been kind of the history and the bar in the past. We certainly would expect to see trends though as well, Andrew.
On the safety side, which is something I really want to pay attention to, too, is you know in the phase I/II 40 mg per kg dose cohort, you did see some SAEs there. Maybe talk about whether those were indeed drug-related or not. Secondly, are you seeing anything funky going on on a blinded basis in your ongoing pivotal study?
Yeah. The safety cases you're talking about were, again, with, as you said, the 40 mg, a higher dose. That had been back in the summer of 2024. We have not seen that type of incident since. That was serious at the time. We investigated it thoroughly. We were not able to rule out the drug. We could not definitively conclude it was due to the drug, but we could not rule it out. That is where we were with that. We provided a safety update again at MDA in March of this last year. That was nearly 1,000 doses in well over 70 patient years. We will provide another safety update with this December update. If there had been something we would consider material, we would have talked about it, but we will provide a fulsome update in December.
Okay. And how do the ex-U.S. regulators view your program? How do you get your drug approved, for instance, in the EU or Japan? What do they care about? What did you see in phase one, two?
We really want to get these medicines to these boys in Europe and in other places of the world, including Japan, as soon as we can. From a base case standpoint, just to set expectations, the bar tends to be higher in Europe for a conditional kind of marketing authorization. So we're assuming a full phase three. We intend to start that phase three this coming year, by the way, because we need a confirmatory trial for our BLA for DMD anyway. You know, we'll have conversations with Europeans and regulators in Japan as well. And that will be the kind of conversation that will be more interesting after we see the data in December. But our base case, full phase three for those locations.
Okay. You did evaluate a whole bunch of functional endpoints back in phase one, two. Which one are you most excited about and banking everything? Or what are you more excited about in terms of the profile you've seen?
I think what we're excited about relates very much to what's most meaningful to these patients and their families. One that is really important in the field is time to rise. If you follow the journey of these patients, when the parents first notice that there's something wrong with their son, it's at a few years old and they're noticing they're having more difficulty getting off the floor than other kids. That's how it gets discovered. By the time the child hits about five seconds to get off the floor, the doctors know that the decline is inevitable. At eight seconds, with exon 51 in particular, it is pretty rapid in terms of the time that they'll be in a wheelchair. Time to rise is an extremely important measure. That data has been, trends in that is very, very important.
The other one that really stands out, particularly for Europe, when you brought up the EMA, is stride velocity 95th centile. The nice piece of that is it's been well validated in the field. The Europeans have accepted it as an endpoint, and they've even defined the MCID as 0.1 m per second. You may notice even in our data at 20 mg per kg at six months, we had exceeded, small data set, but it exceeded that 0.1. That one is an accelerometer on the ankle of these boys that they wear for a couple of weeks. It is not subjective. Very, very important measure as well.
Okay. Best of luck on that data readout, which should open or provide more clarity, it seems like, on the confirmatory trial designs, ex-U.S. regulatory framework and so forth. Shifting gears to DM1 then, you most recently announced in your third quarter earnings a slight delay due to enrollment. What exactly happened and how are you fixing it?
Yeah. You know, in our earnings call, we brought up two things. One, we've been on track and executing well on DMD. We also brought up that we were delayed on DM1 on the enrollment of the Registrational Expansion Cohort. Disappointed in that, to be blunt about it. It is a delay. And it's a delay from the end of the year in which we thought we would fully enroll 60 patients for the Registrational Expansion Cohort of ACHIEVE. That is going to be extended until early Q2 of the following year. So that's the delay. I will mention that we will be initiating our phase III in Q1. That is per plan. Reason for the delay, I put it in twofold. One is we had been using through ACHIEVE, the multi-ascending dose cohort, up to 56 patients.
All of that dose escalation had been done through nine sites, ex-U.S. It had been executed well. We had assumed that when we said, let's add another 60, more than doubling it, that we could just continue to add at each of those sites and they'd be able to continue enrolling at a good pace. Some of the sites ran into some capacity issues. What I mean by that is they needed nurses, they needed somebody else in the pharmacy, things like that. We've been working through that. Should have figured it out sooner, but we worked through it. We've also added two more sites in Europe to deal with the capacity. We also said that we'd be adding some sites in the U.S. simply for later in the year, meaning this year, as some U.S. sites to enable us to hit the 60 faster.
That took us about a month longer than I'd hoped. Those were just basic operational blocking and tackling type things from contract taking longer to sign, for example. We now have three sites in the U.S., two more sites added in Europe. That brings us up to 14 sites. I think that addresses it. We feel confident in the new timelines we've been provided.
Understood. Okay. You did disclose in your 10-Q filing that you're 50% of the way through enrollment out of 60. Is that true?
We're closing in on 50%. That's what we've been working towards.
Okay. We're getting there. Speaking of the study design itself, back in June, I guess you did switch the primary endpoint to vHOT at six months. How can we be sure that there will be no more changes in your study? Can you kind of guarantee us there will be no more changes?
I'm not anticipating any other changes. Let me say that. I do think the switch to vHOT, that was a surprise for us. I know we surprised people with it. We had switched from the splicing as our primary to vHOT, which was our secondary. Now we switched those. We were able to do those fairly seamlessly, add the additional patients, and move forward. I think from the standpoint of feeling good about where we are, we have been enrolling the patients. We're moving forward exactly to the plan. As I mentioned, we'll initiate a phase III in Q1 of this year.
Now with the primary endpoint being vHOT, what exactly are you assuming drug versus placebo behavior out to, I think your endpoint is six months? Are you expecting placebo to move much, for instance?
We took, in terms of doing the powering and the stats, we took a conservative approach with that. We were not assuming some meaningful placebo change. We have taken a number of measures to just take a fairly conservative approach statistically. And also that was one of the reasons we increase the N up to 60. Recorded we were 30 to 40 we increase it all the way up to 60. So it is not depended upon some negative move in placebo.
Got it. In the primary endpoint, I remember you've done analysis based on MMRM versus non-MMRM adjusted. For the primary endpoint, what exactly is the analysis?
We'll do both. We'll do both. We've got assumptions of without MMR, but MMR certainly helps adjust for baseline considerations as well.
Okay. And for you to be able to file an accelerated approval at this juncture, vHOT must be stat-sig and do any of the secondary endpoints, including splicing, can they just show a trend and you're good to go, for instance?
The expectation for AA is that you have a primary endpoint that is statistically meaningful. vHOT, we've powered for that. In AA, the FDA can always use its judgment. They've approved things without stat-sig, but we are powering for stat-sig. We've also powered for statistical significance on splicing correction with CASI. That's a very important measure in this field because it really is kind of addressing the core pathobiology, or it tells you if you're addressing the core pathobiology of the disease. The expectation is that you see trends on other functional features. We've got a number of those that we have seen those trends in the past, and that's what we anticipate.
In fact, by going to 60, not only do we hit on those stats that I just described, but I think it gives us even higher probability of seeing trends on multiple functional features.
Does it make sense to extend the study a little bit just to make sure you have, let's just say, nine months or 12 months, or are you for sure certain on six months you're able to see something?
No, we feel confident about the N of 60 being a meaningful and robust number. You know, I just add to it, Andrew, that you've got the 60 patients that are three to one drug to placebo as part of that study out to six months. We also have the 50 plus, 56 patients that went through the MAD that have all been dose escalated to the registrational dose of 6.8. So you take that 50 plus plus the patients that have been on drug three to one, now you're talking about an overall package that goes to the FDA of over 100 patients that have been on drug. That is not an abbreviated kind of accelerated approval package. That is a very significant number of patients. So we feel good about the overall data set that we'll be generating.
Okay. To be very clear, has the FDA required you to enroll U.S. patients? Is that why you started the U.S. sites or?
No, to be clear, that is not the case. It never was. It's never been a requirement that you had to. I know some people wanted to know there were US patients being enrolled. They are. That wasn't the motivation. It was really to be able to add patients quickly.
As a follow-up, the confirmatory study, like you said, is starting up in Q1 of next year. What would the primary endpoint be like? What exactly, how big of a study, how long of a study, any kind of color would be helpful?
Our Chief Medical Officer, Doug Kerr, is going to, he will unveil that soon. Just to give a bit of a preview is that, look, I think this is going to be a field-defining phase three. I think that's true for DMD, and I think it for DM1, and I mean it. You know, we have vHOT as an intermediate clinical endpoint. We don't see hand myotonia, single-finger hand myotonia for this disease, which is so heterogeneous and also has a major CNS component as being the clinically meaningful primary endpoint for a phase three. It is not going to be our primary endpoint for the phase three.
Instead, it will be based upon the data that we will have generated and have been generating, things like time function tests, five-time sit-to-stand, 10-meter walk-run, others that we can clearly show are clinically meaningful to patients and also have something to do with patient-reported outcomes like CNS outcomes and so on. That will be all part of our phase three. Looking at the CNS aspects will be another major feature of the phase three, which I think will further differentiate the data set that we have at the end of the day.
Can you talk about your desire to be first to market? Does it matter to you? Are you willing to be patient to be second to market? Maybe talk about your strategy for the DM1 program.
Sure. You know, and I think the strategy has been fairly consistent over time. You know, we have been, you know, we started later than one of the competitors that could be first. But we came in with a second-generation targeting moiety, meaning a Fab, which we think will differentiate over time. We think it differentiates in a few ways. One, CNS. Another is splicing, which you need to have sufficient splicing to affect the heterogeneity of the disease and potentially even safety because with a Fab, we're trying to avoid blocking that TFR1 receptor and avoiding anemia that's been typical in this field. Now, with that, we went for accelerated approval to move as quickly as we could while coming behind it with a set of data that I think will be differentiating.
It puts us in a position to come to the market quickly relative to a competitor, but it also gives us a position to come in over time with a very differentiated profile and product. I'm sure you can find plenty of analogs out there where a fast follower in this type of market that has to build can do very, very well in terms of market over time.
Maybe one more question. Obviously, your competitor got taken out. Maybe you talk about big pharma's strategic interest in your name, whether you're getting them. Is it your desire to keep this for yourselves or you want to, you're willing to give it away?
I will make a couple of comments and then I will give my buddy here a chance to say a few words too. Listen, I would not comment too much on strategics. I mean, this company has always had interest from others and the platform is of interest. The approach of the company has been that we really do believe that we are very close to having two assets that could be commercial. There is a lot of synergy between those assets in terms of commercialization. You know, I have been in this type of position before. You always look to do what is in the best interest of the shareholders if there is strategic interest. I think the best approach is for us to be looking to see how we can accelerate these programs and create real significant value for our shareholders as an independent company for now.
Go ahead, Erick.
Yeah, I think we have a tremendous opportunity not only within the DM1 and DMD, as we've been discussing for the last 25 minutes, but also with some of the other products that we haven't really discussed yet. When you look at DMD in particular, once we release this data and hopefully de-risk the platform, there's three other exons, four other exons that we could go after that could triple the TAM in a pretty de-risked manner. In addition, we haven't talked about FSHD, but that's something that's also on our mind. With respect to any kind of strategic transactions, obviously we need to do what's in the best interest of the shareholders. We have a lot of growth ahead of us, even beyond DM1 and DMD, to really build a capital-efficient sales force around muscle disease focused on 100 centers to be.